The skin is the major barrier to the entry of foreign solutes from the environment into the body as well to the loss of heat and moisture from the body. The outermost layer of the epidermis, the stratum corneum, is normally assumed to be the major barrier to drug absorption through the skin. It has also been assumed that the drugs penetrating the epidermis are then removed by the dermal blood supply.
Drugs will not penetrate into deeper tissues after topical application if the stratum corneum barrier is not overcome. Complete removal of this barrier should yield tissue levels equivalent to those observed after dermal application. Singh et al., (1993) referred to in the list of references hereinafter, observed that iontophoresis also yielded tissue concentrations of lignocaine and salicylic acid in vivo, similar to those observed for dermal application.
Iontophoresis is a process which involves the transport of charged substances into body tissue, such as skin, by the passage of an electric current. Transport of solutes by iontophoresis is dependent on many factors, including solute physio chemical factors which includes (ionic charges [Gangarosa et al., 1980; Pikal, 1990; Srinivasan and Higuchi, 1990; Kasting and Keister, 1989; Phipps et al., 1989; Burnette and Ongpipattanakul, 1987; DeNuzzio and Berner, 1990], the presence of extraneous ions [Bellatone et al., 1986], pH of the donor solution [Siddiqui et al., 1985b and 1989; Burnette and Marrero, 1986; Wearley et al., 1989], ionic strength [Lelawongs et al, 100-; Wearley et al., 1989], solute concentration [O'Malley and Oester, 1955; Bellatone et al, 1986; Wearley et al., 1989], buffer constituents, chemical structure of the solute inclusive of conductivity [Siddiqui et al., 1989]); physiological factors (skin region--density of appendages [Roberts et al., 1982; Feldman et al., 1967], age, sex, race, hydration of the skin [Potts et al., 1984], delipidization--ethanol pretreatment [Srinivasan et al., 1989], fluidisation of lipids and permeability of skin [Tregear, 1966; Phipps et al., 1989]) and electrical factors inclusive of current density [Bellatone et al., 1986; DelTerzo et al., 1989], nature of electrodes [Bellatone et al., 1986, Masada et al., 1989], duration of treatment, nature of current [Okabe et al., 1986; Yamamoto and Yamamoto, 1976 and 1978; Chien et al., 1989; Bagniefski and Burnette, 1990; Pikal and Shah, 1991]).
Hitherto there has been described methods and compositions for enhanced skin concentration of iontophoretically delivered active agents. During iontophoresis, charged compounds pass from a reservoir attached to the skin of a person into the tissue underneath. The process is one wherein the rate of delivery is a function of current, active agent concentration and presence of other ions. It is a generally held belief that higher concentrations of active agent, higher levels of current and lower concentrations of other ions result in greater delivery of the active compound. Generally, iontophoretic devices comprise at least two electrodes--both on the surface, an electrical energy source, such as a battery, and at least one reservoir which contains the active agent to be delivered.
Mention can be made to prior art which describes methods and devices involving the internal placement of iontophoretic electrodes into body cavities. Stephen et al., (U.S. Pat. No. 5,222,936) describe a method and apparatus specifically for the placement of an iontophoretic electrode in the form of a tubular catheter into hollow body cavities containing ion-rich physiological fluids, such as the bladder and vagina. The purpose of their invention was to introduce a technique whereby the selection of the active electrode material and drug counterion would be such as to produce ionic species which interact with one another to minimise or reduce the number or water hydrolysis products produced by electrode decay as a result of the iontophoretic process.
Reference can also be made to German Patents 3809814 and 3844518 which describe electrodes designed for implantation into fluid containing hollow body cavities, specifically the bladder, for the local treatment of bladder cancer by iontophoresis. In these specifications, the receptor electrode was enclosed in a type of girdle worn around the lower part of the body and connected to the electrode placed in the bladder. The electrode placed in the bladder comprised a tubular rigid probe having a peripheral wall and opposed rows of delivery apertures in the peripheral wall. The inserted end of the probe was sealed and a conductor passed down the hollow interior of the probe and was connected to a source of current at an outer end.
U.S. Pat. No. 4,411,648 also refers to electrode placement in the bladder to prevent infection. In this case, both donor and receptor electrodes in the form of rigid metal probes were inserted into the bladder and the surrounding bladder contents were sterilised by the ions generated by the decomposition of the electrode when the current was passed. All of the abovementioned references rely upon the presence of a fluid environment around their donor electrodes for the passage of drug solution or generation of heavy metal ions and were specifically concerned with delivery of the drug solution to the relevant body cavity.
Reference may be made to other prior art concerning location of one electrode on the skin of a subject and the location of another electrode such as a probe or needle electrode in a body cavity or body tissue which is described in International Publication WO94/05369. This specification describes a probe type electrode which may have a needle or trocar attached thereto which has a selectively permeable membrane through which a drug may be driven by a voltage gradient to deliver a drug to a target area of an internal body tissue. The iontophoresis apparatus described in this reference may be utilised to deliver a drug to a tumour. International Publication WO91/16945, International Publication WO94/05361 and U.S. Pat. No. 3,491,755 describe similar iontophoresis apparatus.
Reference may also be made to EP 0438078 which describes a probe electrode or catheter having an internal cavity in which is located an internal wire electrode and a plurality of holes or apertures in a side wall of the cavity to allow for passage of a drug from an internal cavity to a body cavity or organ. A counter-electrode may be placed on the outside of the body on the skin as close as possible to the organ subjected to the iontophoretic treatment.
FR 2516388 describes a similar probe electrode or catheter to that described in EP 0438078 which may be fitted with a needle in the catheter for iontophoresis injection into physiological joints. The catheter may be provided with internal electrodes spaced from each other and located in a side wall of the catheter and flush with an internal surface of the side wall.
Reference also may be made to EP 0378132 which refers to iontophoresis needle electrodes.
In summary of the abovementioned prior art, it will be appreciated that the donor or active electrode which was responsible for drug delivery and the receptor or inactive electrode has been utilised in a variety of situations which include:
(i) adjacent each other in topical applications such as the epidermis; PA1 (ii) the active electrode being inserted in a body cavity while the inactive electrode was placed on the skin; or PA1 (iii) where both electrodes were inserted in the same or different body cavities.
However, it has now been discovered that an iontophoresis technique may be applied for effective administration of a drug to sensitive tissues such as the eye, ear inclusive of the eardrum, nose or throat in a non-invasive manner to avoid the use of invasive administration techniques such as direct injection of the drug into the sensitive tissue which is often painful or traumatic and is also risky because, if not administered satisfactorily, may result in serious injury.